CN110522722A - 一种纳米诊疗剂及其制备方法与应用 - Google Patents
一种纳米诊疗剂及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开一种纳米诊疗剂及其制备方法与应用,其中,所述纳米诊疗剂包括金纳米囊泡和化疗药物,所述金纳米囊泡包括囊泡膜和镶嵌于所述囊泡膜内的金纳米颗粒,所述金纳米囊泡具有空腔结构,所述化疗药物装载于所述空腔内;所述囊泡膜的材料为结构如下式所示的聚合物,其中m=45,n=200‑350;本发明的纳米诊疗剂具有良好的光热转化能力,可以实现对肿瘤部位的光热治疗;同时该纳米诊疗剂生物可降解,具有光控释放的特点,能够在肿瘤部位释放出装载的化疗药物,实现对肿瘤部位的化学治疗。光热治疗和化学治疗的协同治疗,克服了单一的光热治疗或化学治疗有的局限性,实现更高效的肿瘤治疗效果。
Description
技术领域
本发明涉及医用纳米材料领域,尤其涉及一种纳米诊疗剂及其制备方法与应用。
背景技术
近年来,聚合物囊泡由于其独特的物理或者化学性质已引起了科学界的广泛关注,并在药物运输、基因递送、分子影像诊疗一体化等领域展现出巨大的潜力,已经广泛地用于智能诊疗剂的设计和构建。在特定外界刺激下,聚合物囊泡的某些理化性质能够发生变化,因而,可以通过调节外界刺激信号的开与关、信号的强度和类型来实现对其的智能调控,但是同时它也存在一些问题,如聚合物囊泡的稳定性差,容易破裂和降解。因此,提高囊泡的稳定性有助于其进一步生物医学应用。最近的研究表明,在囊泡的膜中添加无机纳米材料,可以有效地增强其稳定性。
基于贵金属纳米材料的表面等离子共振效应,在激光照射下,可以将光能转换为热能,从而实现光热治疗。对于金纳米颗粒而言,10nm颗粒的吸收峰在520nm处,100nm颗粒的吸收峰在580nm处,由于它们的吸收峰不在NIR(近红外)区,使用金纳米颗粒对肿瘤进行光热治疗,光热转换效率低下,穿透能力低下。
金纳米囊泡的生物应用是近几年的研究热点之一。新加坡南洋理工大学DuanHongwei教授组通过亲水性的聚乙二醇和疏水性的聚(丙烯酸-2-硝基苄基酯)修饰金纳米颗粒,制备得到装载阿霉素盐酸盐的金纳米囊泡用于肿瘤光热和化学的协同治疗。林静教授组曾利用双亲两嵌段聚合物修饰金纳米颗粒,自组装形成金纳米囊泡并装载光敏剂二氢卟吩,用于光声指导下的肿瘤光热和光动力协同治疗。但是现有的金纳米囊泡所使用的聚合物的疏水链多为聚苯乙烯,由于苯环的存在,空间位阻较大,金纳米颗粒之间靠近程度有限,以至于表面等离子耦合效应有限,光热转换效率有待提高。
因此,现有技术还有待于改进和发展。
发明内容
鉴于上述现有技术的不足,本发明的目的在于提供一种纳米诊疗剂及其制备方法与应用,旨在解决现有纳米诊疗剂存在稳定性差与光热转化效率较低的问题。
本发明的技术方案如下:
一种纳米诊疗剂,其中,包括金纳米囊泡和化疗药物,所述金纳米囊泡包括囊泡膜和镶嵌于所述囊泡膜内的金纳米颗粒,所述金纳米囊泡具有空腔结构,所述化疗药物装载于所述空腔内;
所述囊泡膜的材料为结构如下式所示的聚合物,其中m=45,n=200-350;
进一步地,所述金纳米颗粒包括金纳米球、金纳米杯、金纳米笼、金纳米棒、金纳米片、金纳米壳、金纳米膜和金纳米花中的一种或多种。
进一步地,所述化疗药物包括阿霉素盐酸盐、紫杉醇、喜树碱、长春新碱、柔红霉素、噻替哌、6-巯嘌呤、溶癌呤、地塞米松、5-氟尿嘧啶、顺铂、卡铂、丝裂霉素、多西紫杉醇和培美曲赛中的一种或多种。
进一步地,所述金纳米囊泡的直径为90-500nm。
进一步地,所述聚合物和金纳米颗粒的质量比为1:1-1:5。
一种制备本发明所述的纳米诊疗剂的方法,其中,包括步骤:
将金纳米颗粒溶液加入到聚合物溶液中,使金纳米颗粒和聚合物交联,将交联产物溶于四氢呋喃中;
除去所述四氢呋喃,得到薄膜;
将化疗药物水溶液加入至所述薄膜中,并超声至溶液变澄清,得到纳米诊疗剂。
进一步地,用氮气流除去所述四氢呋喃。
进一步地,所述超声至溶液变澄清的时间为1-5min。
进一步地,所述化疗药物水溶液中,化疗药物的浓度为0.05mg/mL-3mg/mL。
一种本发明所述的纳米诊疗剂在制备治疗肿瘤的制剂中的应用。
有益效果:本发明所述纳米诊疗剂中,由于聚合物拉近了金纳米颗粒之间的距离,金纳米颗粒之间的表面等离子耦合效应增强,金纳米囊泡的吸收红移到近红外处,光热转化效率增强,穿透深度增加。同时因为金纳米囊泡具有空腔结构,可以在其空腔内部装载化疗药物等实现对肿瘤的协同治疗。
附图说明
图1为本发明具体的实施例中聚合物FmocHN-PEG-b-PCL-TE的合成路线图。
图2为本发明具体的实施例中纳米诊疗剂的扫描电镜图。
图3为本发明具体的实施例中纳米诊疗剂的体外光热升温曲线图。
图4为本发明具体的实施例中金纳米囊泡装载阿霉素盐酸盐释放曲线图。
图5为本发明具体的实施例中光热/化疗协同治疗对U-87MG肿瘤细胞的杀伤曲线图。
图6为本发明具体的实施例中纳米诊疗剂注射入老鼠体内前后体内光声成像效果对比图。
图7为本发明具体的实施例中光热/化疗协同治疗对U-87MG肿瘤生长的抑制曲线图。
具体实施方式
本发明提供一种纳米诊疗剂及其制备方法与应用,为使本发明的目的、技术方案及效果更加清楚、明确,以下对本发明进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
本发明提供一种纳米诊疗剂,其中,包括金纳米囊泡和化疗药物,所述金纳米囊泡包括囊泡膜和镶嵌于所述囊泡膜内的金纳米颗粒,所述金纳米囊泡具有空腔结构,所述化疗药物装载于所述空腔内;
所述囊泡膜的材料为结构如下式所示的聚合物,其中m=45,n=200-350;
本发明中,所述聚合物为双亲两嵌段聚合物FmocHN-PEG-b-PCL-TE,所述聚合物的末端为硫辛酸修饰。在一种优选的实施方式中,所述聚合物中,n=270。该链长的聚合物更容易形成金纳米囊泡。
现有的金纳米囊泡所使用的聚合物的疏水链多为聚苯乙烯,由于苯环的存在,空间位阻较大,金纳米颗粒之间靠近程度有限,以至于表面等离子耦合效应有限,光热转换效率较低。与现有相比,本发明金纳米囊泡中,所使用的聚合物的疏水链为聚己内酯,聚己内酯空间位阻较小,可以把金纳米颗粒之间的距离拉得更近,从而使得金纳米颗粒之间的表面等离子耦合效应增强,金纳米囊泡的吸收红移到近红外处,光热转化效率增强,穿透深度增加。另外,本发明所述聚合物材料易降解,容易被体内清除。
本发明纳米诊疗剂中,由于囊泡膜内镶嵌金纳米颗粒,使得囊泡的结构稳定性增强,能有效避免药物泄露。同时由于聚合物把金纳米颗粒之间的距离拉近,囊泡膜中相邻金纳米颗粒间存在表面等离子耦合效应而具有很强的光热作用,可以增强光声和超声成像。囊泡本身有空腔结构,有利于药物的装载,具有很高的载药能力且囊泡表面易功能化,便于生物分子进一步修饰,实现靶向治疗。这一智能纳米诊疗剂在光作用下,囊泡解体成小的纳米颗粒单元,且颗粒表面的聚合物材料易降解,容易被体内清除。装载化疗药物的生物可降解的金纳米囊泡体系可实现响应性药物释放功能与化疗-光热协同治疗功能的有效结合,有望提高肿瘤的治疗效果并降低毒副作用。
在一种实施方式中,所述金纳米颗粒包括金纳米球、金纳米杯、金纳米笼、金纳米棒、金纳米片、金纳米壳、金纳米膜和金纳米花等中的一种或多种。在一种优选的实施方式中,所述金纳米颗粒为金纳米球,因为金纳米球制备方法成熟,易于大量制备。更优选的,所述金纳米球的粒径为26nm。
本发明化疗药物装载在金纳米囊泡的空腔内部。在一种实施方式中,所述化疗药物包括阿霉素盐酸盐、紫杉醇、喜树碱、长春新碱、柔红霉素、噻替哌、6-巯嘌呤、溶癌呤、地塞米松、5-氟尿嘧啶、顺铂、卡铂、丝裂霉素、多西紫杉醇和培美曲赛等中的一种或多种。在一种优选的实施方式中,所述化疗药物为阿霉素盐酸盐。
在一种实施方式中,所述金纳米囊泡的直径为90-500nm。
在一种优选的实施方式中,所述聚合物和金纳米颗粒的质量比为1:1-1:5。此质量比下聚合物和金纳米囊泡的交联效率较高。
本发明提供一种制备本发明所述的纳米诊疗剂的方法,其中,包括步骤:
将金纳米颗粒溶液加入到聚合物溶液中,使金纳米颗粒和聚合物交联,将交联产物溶于四氢呋喃中;
除去所述四氢呋喃,得到薄膜;
将化疗药物水溶液加入至所述薄膜中,并超声至溶液变澄清,得到纳米诊疗剂。
本发明利用双亲两嵌段聚合物FmocHN-PEG-b-PCL-TE修饰金纳米颗粒,通过自组装形成金纳米囊泡,同时装载化疗药物。所述金纳米囊泡稳定性好,光热转换效率高;所述纳米诊疗剂能够同时实现肿瘤的光声成像和超声成像,以及肿瘤的光热治疗与化学治疗相结合的协同治疗。另外,本发明制备工艺简单、操作方便,不需要复杂昂贵的设备,易于实现工业化生产,因此在光声成像、药物递送、癌症协同治疗等领域将具有良好的应用前景。
在一种实施方式中,用氮气流除去所述四氢呋喃。
在一种优选的实施方式中,所述超声至溶液变澄清的时间为1-5min。此条件下金纳米囊泡易于形成。
在一种优选的实施方式中,所述化疗药物水溶液中,化疗药物的浓度为0.05mg/mL-3mg/mL,此浓度下化疗药物不影响金纳米囊泡的形成且装载效率高。
本发明提供一种本发明所述的纳米诊疗剂在制备治疗肿瘤的制剂中的应用。
本发明提供一种本发明所述的纳米诊疗剂在制备光声和超声造影剂中的应用。
下面通过具体的实施例对本发明进一步说明。
本实施例中金纳米囊泡的制备过程如下:
1、合成26nm的金纳米颗粒
将250mL的超纯水,500μL 50mg/mL HAuCl4·3H2O水溶液转入圆底烧瓶中,混合液加热至沸腾,在稳定的转速下加入10mL的1%质量比的柠檬酸钠水溶液进行还原,反应30min,溶液由淡黄色转变为红色,得到19nm金纳米颗粒。将反应温度降至90℃,迅速加入500μL 50mg/mL HAuCl4水溶液,和10mL的1%柠檬酸钠水溶液,重复两次,得到26nm金纳米颗粒。
2、合成聚合物FmocHN-PEG-b-PCL-TE
在圆底烧瓶中加入50mg FmocHN-PEG2000-OH,770mg己内酯,无水无氧的条件下加入1滴乙酸锌(SnOct)作为引发剂,135℃反应18h,得到FmocHN-PEG-b-PCL。产物在无水乙醚条件下沉淀出。
将干燥的400mg FmocHN-PEG-b-PCL,15mg N,N-二环己基碳酰亚胺(DCC),2mg 4-二甲氨基吡啶(DMAP),12mg硫辛酸共同放入三颈瓶中,加入2mL二氯甲烷作为反应液,反应至过夜,得到FmocHN-PEG-b-PCL-TE。产物在正己烷条件下沉淀出。
合成聚合物FmocHN-PEG-b-PCL-TE的步骤路线图如图1所示。
3、合成纳米诊疗剂
取50mL的26nm金纳米颗粒溶液离心浓缩,去掉多余的水溶液。将5mg聚合物溶解到10mL N,N-二甲基甲酰胺中,得到聚合物溶液。浓缩后的金纳米颗粒溶液在超声的条件下缓慢的加入到聚合物溶液中,超声1h,结束后静置过夜,使金纳米颗粒和聚合物充分交联。将修饰好聚合物的金纳米颗粒转移至离心管中,用四氢呋喃多次反复清洗,除去多余的聚合物。最后将修饰好聚合物的金纳米颗粒复溶在10mL的四氢呋喃中。
取500μL修饰好的聚合物的金纳米颗粒的四氢呋喃溶液,转移至小样品瓶中,通入稳定的氮气流除去四氢呋喃,得到均一的薄膜层,迅速将1mL 1mg/mL的阿霉素盐酸盐水溶液加入至样品瓶中,在超声的条件下超声直至溶液变为澄清,得到装载有阿霉素盐酸盐的金纳米囊泡,即纳米诊疗剂。
合成的纳米诊疗剂如图2所示。从图2可知,所合成的纳米诊疗剂为圆球形状,所述纳米诊疗剂的粒径为100nm-300nm之间。
本实施例中纳米诊疗剂的性能检测如下:
1、纳米诊疗剂的光热效果检测
分别配置紫外吸光系数OD@808=0.1,OD@808=0.2,OD@808=0.4,OD@808=0.5浓度的金纳米囊泡,准备相同体积的超纯水作为对照组。使用808激光器分别照射5min,用热成像仪监测纳米诊疗剂的升温效果。
纳米诊疗剂的光热效果如图3所示,从图3可知,随着纳米诊疗剂浓度的提高,光热效果增加,当纳米诊疗剂的浓度增加到紫外吸光系数OD@808=0.5时,温度可升至65℃。
2、纳米诊疗剂光照促进药物释放效果评价
制备紫外吸光系数OD@808=0.5的纳米诊疗剂8组,分别使用808激光器照射0、2、4、6、8、10、20、30分钟,离心取上清液,用荧光分光光度计测量上清液中DOX的荧光强度,比较标准图谱,计算出释放出的阿霉素盐酸盐的含量。
金纳米囊泡中阿霉素盐酸盐的的释放如图4所示,从图4可知,照射装载有阿霉素盐酸盐的金纳米囊泡10分钟后,阿霉素盐酸盐被释放出50%。
3、光热治疗和化疗协同治疗对U-87MG肿瘤细胞的毒性评价
采用标准的MTT法,评价光热治疗和化疗协同治疗对U-87MG细胞存活率的影响。U-87MG细胞以每孔5×103密度接种到96孔板中,并置于37℃、5%CO2条件下培育24h。接着,吸出96孔板中的旧培养基,分别加入含有300μg/mL DGV的DMEM培养基。继续培养24h后,吸出96孔板中的旧培养基,在每个孔加入100μL DMEM培养基,然后对光照孔的每一个孔都使用808nm的激光器照射细胞5分钟,功率为1W/cm2。照射完后,吸出96孔板中的旧培养基,在每个孔中加入100μL含10%MTT的培养基溶液,继续培养1个小时。然后在Bio-Tel EL×800型酶标仪上检测每孔的OD值(检测波长为490nm),用如下公式计算细胞存活率。细胞存活率(cell viability)(%)=(样品的OD490值/空白OD490值)×100%,实验结果见图5。
如图5所示,随着纳米诊疗剂药物浓度的升高,U-87MG细胞存活率(cellviability)会逐渐降低,这是由于化疗药物阿霉素盐酸盐(DOX)的作用。而进行光照后的细胞,细胞存活率(cell viability)会更显著地降低,说明光照使金纳米囊泡产生了光热效果,杀死大量的肿瘤细胞。
4、所有的实验操作均按照临床中心动物保健和使用委员会通过的动物使用和保健制度。雌性Balb/c裸鼠(3周,15-20g),在裸鼠腿皮下注射2×106U-87MG肿瘤细胞,建立小鼠皮下瘤模型。当肿瘤体积达60mm3时,将300μL DGV PBS溶液,通过瘤内注射的方式注入小鼠体内,利用小动物光声成像仪(Vevo LAZR)检测肿瘤区的光声信号变化。实验结果见图6。如图6所示,合成的纳米诊疗剂DGV具有很强的光声效果。
5、光热/化疗协同治疗对U-87MG肿瘤生长的抑制效果评价
雌性Balb/c裸鼠(3周,15-20g),在裸鼠后腿皮下注射2×106U-87MG肿瘤细胞,建立小鼠皮下瘤模型。当肿瘤体积达60mm3时,进行治疗实验。荷瘤小鼠随机分为六组:(1)空白组(Ctrl);(2)注射纯金纳米囊泡(GV)组;(3)注射装载有DOX的金纳米囊泡(DGV)组;(4)注射单纯的DOX组(DOX);(5)注射纯金纳米囊泡+激光组(GV-L);(6)装载有DOX的金纳米囊泡+激光组(DGV-L)每隔一天用游标卡尺测量肿瘤体积,同时监测小鼠的体重,并按照公式V=AB2/2计算肿瘤体积(Tumor volume),其中A是肿瘤的长径,B是肿瘤的短径(mm)。每次测量结果均通过处理前的起始肿瘤体积归一化。实验结果见图7。
图7中表示不同治疗组肿瘤体积(Normalized tumor volume)随时间(天数)的变化情况,注射装载有DOX的金纳米囊泡+激光组(DGV-L)能够显著抑制肿瘤的生长,注射纯金纳米囊泡(GV)组和注射装载有DOX的金纳米囊泡(DGV)组的抑瘤效果较差;14天后,注射装载有DOX的金纳米囊泡+激光组小鼠(DGV-L)的瘤子重量明显低于空白组(Ctrl)、注射纯金纳米囊泡(GV)组以及注射装载有DOX的金纳米囊泡(DGV)组。
由上述可知,本实施例所述的装载有DOX的金纳米囊泡(DGV)纳米诊疗剂可同时实现肿瘤的光声成像以及肿瘤的光热治疗与化学治疗相结合的协同治疗。
综上所述,本发明的纳米诊疗剂,可实现响应性药物释放功能与化疗-光热协同治疗功能的有效结合,有望提高肿瘤的治疗效果并降低毒副作用。
应当理解的是,本发明的应用不限于上述的举例,对本领域普通技术人员来说,可以根据上述说明加以改进或变换,所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (10)
1.一种纳米诊疗剂,其特征在于,包括金纳米囊泡和化疗药物,所述金纳米囊泡包括囊泡膜和镶嵌于所述囊泡膜内的金纳米颗粒,所述金纳米囊泡具有空腔结构,所述化疗药物装载于所述空腔内;
所述囊泡膜的材料为结构如下式所示的聚合物,其中m=45,n=200-350;
2.根据权利要求1所述的纳米诊疗剂,其特征在于,所述金纳米颗粒包括金纳米球、金纳米杯、金纳米笼、金纳米棒、金纳米片、金纳米壳、金纳米膜和金纳米花中的一种或多种。
3.根据权利要求1所述的纳米诊疗剂,其特征在于,所述化疗药物包括阿霉素盐酸盐、紫杉醇、喜树碱、长春新碱、柔红霉素、噻替哌、6-巯嘌呤、溶癌呤、地塞米松、5-氟尿嘧啶、顺铂、卡铂、丝裂霉素、多西紫杉醇和培美曲赛中的一种或多种。
4.根据权利要求1所述的纳米诊疗剂,其特征在于,所述纳米诊疗剂的直径为90-500nm。
5.根据权利要求1所述的纳米诊疗剂,其特征在于,所述聚合物和金纳米颗粒的质量比为1:1-1:5。
6.一种制备如权利要求1-5任一项所述的纳米诊疗剂的方法,其特征在于,包括步骤:
将金纳米颗粒溶液加入到聚合物溶液中,使金纳米颗粒和聚合物交联,将交联产物溶于四氢呋喃中;
除去所述四氢呋喃,得到薄膜;
将化疗药物水溶液加入至所述薄膜中,并超声至溶液变澄清,得到纳米诊疗剂。
7.根据权利要求6所述的方法,其特征在于,用氮气流除去所述四氢呋喃。
8.根据权利要求6所述的方法,其特征在于,所述超声至溶液变澄清的时间为1-5min。
9.根据权利要求6所述的方法,其特征在于,所述化疗药物水溶液中,化疗药物的浓度为0.05mg/mL-3mg/mL。
10.一种权利要求1-5任一项所述的纳米诊疗剂在制备治疗肿瘤的制剂中的应用。
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